Cardiovascular disease is the leading cause of death, and one of the primary causes of disability worldwide. Atherosclerosis is the primary contributor to cardiovascular disease. About one-half of the deaths that can be attributed to cardiovascular disease arise from acute cardiac events, including myocardial infarction. Patients are often treated through percutaneous coronary intervention procedures, including angioplasty and stent placement. Unfortunately, reocclusion of the vessel (restenosis) is a major limitation of such procedures. PTEN (phosphatase and tensin homolog deleted from chromosome 10) has been proposed as a potential target to inhibit post-angioplasty vascular smooth muscle cell (SMC) proliferation and migration, which leads to pathological vascular remodeling and restenosis. We have recently identified a novel class of compounds that selectively inhibit highly proliferative cells through upregulation of PTEN levels. We, therefore, hypothesize that these novel compounds may be effective in attenuating restenosis. In addition, oxidative stress has been implicated as a contributor to neointimal hyperplasia following percutaneous coronary intervention procedures. We propose an additional hypothesis that these compounds can be further modified to include a pro-nitroxyl functional group, which may reduce the oxidative stress imposed upon the injured vascular tissue, as well as to the downstream cardiac tissues, thereby protecting the entire cardiovascular system during the revascularization process. Limited preliminary experiments have shown very promising results, suggesting "minimal risk with high return" for the development of this innovative approach to treating both restenosis and ischemia/reperfusion injury at the same time. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the leading cause of death, and one of the primary causes of disability worldwide. Atherosclerosis is the primary contributor to this disease. Patients suffering from the disease are often treated using angioplasty and stent placement. Unfortunately, restenosis continues to be a long-term complication of these procedures due to vascular smooth muscle cell proliferation and migration. We have recently identified a novel compound that inhibits the growth of highly proliferative cells through a mechanism that has been proposed as a target to prevent vascular remodeling and restenosis. We, therefore, intend to test this idea using the new compound in a pig model of cardiovascular disease. In addition, about one-half of the deaths attributed to cardiovascular disease are due to acute cardiac events, including heart attack. The new compound, which includes a pro-nitroxyl functional group, could also be used to provide antioxidant protection to the heart, preventing additional damage during the reperfusion period following a heart attack. We propose to investigate the development of this multimodal approach to prevent the debilitating post- revascularization cardiovascular events.